6-fluoro steroids



United States 6-FLUORO STEROIDS Raymond L. Pederson and Milton E. Herr, Kalamazoo, John C. Babcock, Portage Township, Kalamazoo County, and J Allan Campbell and John A. Hogg, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application February 19, 1958 Serial No. 716,026

38 Claims. (Cl. 260-2395) The present invention relates to new steroids and is more particularly concerned with 6aand 6/3-fluorinated wherein R represents methyl or hydrogen, R represents hydroxyl, OAcyl or ketonic oxygen and Z represents hydrogen, hydroxyl or ketonic oxygen. The term Acyl as used herein refers to an acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, con taining from one to twelve carbon atoms, inclusive.

It is an object of the present invention to provide novel 6-fluoro-17fl-hydroxy-4-androsten-3-ones, 6-fiuoro-17fl-hydroxy 4 androstene 3,11 diones, 6 fluoro 1113,175- dihydroxy-4-androsten-3-ones, their corresponding 19-nor compounds and the 17-acylates thereof, 6-fiuoro-4-androstene-3,17-diones, 6-fiuoro-1 1B-hydroXy-4-androstene-3,17- diones, 6-fluoro-4-androstene-3,l1,17-triones, their corresponding 19-nor compounds, and novel steroid intermediates used in the preparation thereof and novel processes for the preparation thereof. Other objects will be apparent to those skilled in the art to which this invention pertains.

of other compounds, represented by Formulas 11, I11,

and IV, according to the following equations:

CH CH3 O: I: 0- II F l where H HA G113 CH:

O III HO IV wherein R, R and Z have the same meaning as given above.

The compounds represented by Formula II, for example, the 6-fluoro-17p-hydroxy-1,4-androstadien-3-ones and 6-fiuoro-17B-hydroxy-19-nor-1,4-androstadien-3-ones can be obtained by dehydrogenation of the corresponding starting compound of Formula 1. However, those compounds of Formula II where R equals hydrogen, for example, 6-fluoro-17fi-hydroxy-19-nor-1,4-androstadien-3- ones, are unstable and spontaneously rearrange to produce the compounds of Formula IIA, for example, 6- fluoro l9 nor 1,3,5(10) androstatriene 3,175 diols [6 fluoro 1,3,5(10) estratriene 3,175 diols]. The compounds of Formula IIA possess estrogem'c, antioste- .oporotic, anti-inflammatory and CNS regulating propnium dioxide according to methods generally known for l-dehydrogenating hydrocortisone or biologically using a fungus, for example, Septomyxa affim's A. T. C. C. 6737, in accordance with the procedure disclosed in Belgian Patent No. 545,877.

The conversion of the compounds of Formula I to the compounds of Formula III, for example, the 6-fluoro- 17/3-hydroxyandrostan-3-ones and 6-fiuoro-17B-hydroxy- 19-nor-androstan-3-ones is accomplished by catalytic hydrogenation of the corresponding starting compound of Formula I using a noble metal, preferably palladium, as catalyst. The reaction can be carried out at atmospheric or lower pressures and in the presence of an organic solvent, such as ethyl acetate. The thus-obtained compounds of Formula III can then be treated with a metal hydride, for example, lithium aluminum hydride or a metal borohydride, preferably an alkali-metal horohydride, suchas sodium borohydride, in the presence of an organic solvent, such as dioxane, at room temperature, to produce the compounds of Formula IV, such as 6- fiuoro-3 3,17/3-dihydroxandrostanes and 6-fiuoro-3;8,l7fidihydroxy-l9-norandrostanes.

The novel products of this invention, the compounds of Formula I, possess therapeutic properties. The compounds of Formula I demonstrate anabolic and androgenic activity. For example, 6a-fiuoro-l7B-hydroxy-4-androsten-3-one l7-propionate (6ot-tluorotestosterone propionate) exhibits essentially the same anabolic activity but only 33 percent of the androgenic potency of l7fi-hydroxy-4-androsten-3-one l7-propionate (testosterone propionate). Thus, the 6a-fiuoro substituted compound produces a three-fold increase in therapeutic ratio and is a potent preferentially anabolic compound. The compounds of Formulas II, III, and IV also possess androgenic and anabolic activity. Moreover, the compounds of Formulas I, II, III, and IV also possess antiestrogenic, antiosteoporotic and CNS regulating properties. Administration of the steroids of Formulas I, II, III, and 1V can be in conventional dosage forms, such as pills, tablets, capsules, syrups or elixirs for oral use, or in liquid forms which are adaptable to the natural and synthetic steroid-hormones for injectable products.

The novel steroids of Formula I can be prepared according to the following reaction sequence:

CH1 GHi RI (I) O Iad O 0= 31 OH; CHl/RI O O O'- HO- R R g:

XVI O XV HIC IIT R (53-1 on, {e 0 1L O l)n' CH: CH: OH (i) XVII I019 HIC IIT t O:

(Aka/CH2 2% CH3 C 9 OH OAcyl no? no R R I f Iaf(ester) O- 0:

wherein R and R have the same meaning as previously 65 given, R is an alkylene radical containing not more than eight carbon atoms, inclusive, and the attaching oxygen to carbon bonds are separated by a chain of at least two and not more than three carbon atoms, and A-cyl is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid, containing from one to twelve carbon atoms, inclusive, Y is hydrogen or ketonic oxygen and n and n are whole numbers from one to two, inclusive.

low, the reactions embodied in the processes characterizing this invention are susceptible of variation in the specific steps leading to the products of this invention, the precise sequence selected being determined by such factors as economics and convenience.

One of the processes of the present invention comprises treating compounds of the type represented by Formulae Va and Vb such as 17fi-hydroxy-4-androsten-3- one and 17fl-hydroxy-4-androstene-3,1l-dione, respectively, and their corresponding 19-nor compounds, with As indicated above and described in greater detail be- 75 ethylene glycol in the presence of a strong acid as catalyst,

v V such as toluenesulfonic acid, ortho-chlorobenzenesulfonic acid, sulfuric acid, and the like, to obtain the corresponding 3-ethylene ketals represented by Formulae VIa and VIb such as 17 3-hydroxy-5-androsten-3-one 3-ethylene ketal and 17 3-hydroxy-5-androstene-3,1l-dione 3-ethylene ketal, respectively, and their corresponding 19-nor compounds. Similarly the compounds of Formulae Va and Vb can be reacted with other 1,2-alkane diols or 1,3- alkane diols such as propylene glycol, butane-1,2-diol, butane-1,3-diol, pentane-1,2- and 1,3-diol, hexane-1,2- and 1,3-diol, heptane-1,2- and 1,3-diol, octane-1,2- and 1,3-diol, or other alkane diols of the formula:

wherein n" is an integrer having a value of from one to two, inclusive, and R and R are selected from the group consisting of hydrogen and lower alkyl radicals containing up to six carbon atoms, and wherein the total number of carbon atoms in the alkane diol is up to and including eight carbon atoms, to obtain the corresponding 3-alkylene ketals of the compounds of Formulae Va and Vb.

The compounds of Formulae Wu and VIb are then treated with a peracid such as peracetic acid or perbenzoic acid to obtain the corresponding 5,6-epoxy compounds represented by Formulae VIIa and VIIb, such as 5a,6a. epoxy-17,6-hydroxyandrostan-3-one 3-ethylene ketal and 5a,6a-epoxy-17fl-hydroxyandrostane-3,1l-dione 3-ethylene ketal, respectively, and their corresponding 19-nor compounds.

'The thus-obtained compounds of Formulae VIIa and- VIIb, are then treated with a fluorine releasing agent such as hydrofluoric acid, preferably in the presence of an organic solvent, such as methylene chloride, to obtain the compounds of Formulae VIIIa and VIIIb, such as 6,8- fluoro-5a,17,19-dihyd1'oxyandrostan-3-one and oft-fluoro- Sa,17/3-dihydroxyandrostane-3,1l-dione, respectively, and their corresponding 19-nor compounds.

The compounds of Formulae VIIIa and VIIIb are then subjected to treatment with an esterifying agent to obtain the 17-acylates represented by Formulae IXa and IXb, such as the 6,8-fiuoro-5a,1718-dihydroxyandrostan-3-one 17-acylates and GB-fluoro-Sa,17/8-dihydroxyandrostan- 3,11-dione 17-acylates, respectively, and their corresponding 19-nor compounds. Suitable esterifying agents are organic carboxylic acids, particularly hydrocarbon carboxylic acids, containing from one to twelve carbon atoms, inclusive, or the acid anhydrides and acid halides thereof. For example, a saturated straight-chain aliphatic acid, e. g., formic, acetic, propionic, butyric, valeric, hexanoic, lauric, a saturated branched-chain aliphatic acid, e. g., trimethylacetic, isobutyric, isovaleric, tertiary butylacetic, a cycloaliphatic saturated acid, e. g., fl-cyclopentylpropionic, cyclohexane-carboxylic, cyclohexylacetic, an alkaryl acid, e. g., benzoic, phenylacetic, p-phenylpropionic, 0-, m-, and p-toluic, a saturated dibasic acid (which can be converted into water-soluble, e. g., sodium, salts), e. g., succinic, adipic; a monobasic unsaturated acid, e. g., acrylic, crotonic, undecylenic, propiolic, undecolic, cinnamic; dibasic unsaturated acids (which can be converted into water-soluble, e. g., sodium, salts), e. g., maleic and citraconic, or the acid anhydrides and acid halides thereof, can be used to esterify the compounds of Formulae VIHa and VIIIb to' convert them into the compounds of Formulae IXa and IXb. If the esterifying agent is the free acid, the reaction is preferably effected in the presence of an esterification catalyst, for example, p-toluenesulfonyl chloride, trifiuoroacetic anhydride, p-toluenesulfonic acid, trifluoroacetic acid, sulfuric acid, and the like. i

The compounds of Formulae IXa and IXb are then de hydrated, preferably with a halo amide or imide of an aliphatic acid, such as N-bromoacetamide, N-chlorosuccinimide, or N-bromosuccinimide, dissolved in pyridine, dioxane, or other suitable solvents and in the presence of an anhydrous form of sulfur dioxide to produce the compounds of Formulae Ifia(ester) and I/3b(ester) such as 6fl-fluoro-l7/i-hydroxy-4-androsten-3-one 17acylates and 6/8-fluoro-l7B-hydroxy-4-androstene-3,1l-dione 17- acylates, respectively, and their corresponding 19-n0r compounds. The anhydrous sulfur dioxide can be in the form of gaseous or liquid sulfur dioxide or in the form of a material which, in situ, produces sulfur dioxide, as, for example, an alkali-metal hyposulfite.

The dehydration of the compounds of Formulae IXa and IXb can also be effected in alkali solution or in acidic solution. Suitable acid dehydrating agents include mineral acids, such as, for example, hydrochloric acid and sulfuric acid. Acetic anhydride, acetic acid, p-toluene sulfonic acid, or thionyl chloride in pyridine are also suitable as dehydrating agents. Basic dehydrating agents include, for example, alkali and alkaline earth metal hydroxides such as sodium, potassium, barium, and calcium hydroxides, and the like.

The compounds of Formulae I;8a(ester) or IBb(ester), are then isomerized to the corresponding 60(r'fl1l01'0 compounds of Formulae Ioa(ester) or Iocb(ester), such as 6afluoro-l7fi-hydroxy-4-androsten-3-one l7-acylates or 6ozfluoro-17B-hydroxy-4-androstene-3 l l-dione 17-acylates, respectively, and their corresponding 19-nor compounds, by treating the I;8a(ester) or I;3b(ester) compounds at temperatures of Zero degrees centigrade or slightly lower in a liquid medium, such as an organic solvent, for example, chloroform, methylene chloride, ether, and the like, and in the presence of prototropicagents (proton donating agents) such as Water, alcohols, organic acids, and the like, with a mineral acid, such as hydrogen chloride. The reaction mixture obtained can then be washed with water and concentrated to give a residue containing Iaa(ester) or Ia.b(ester).

Alternatively, the compounds of Formulae Iaa(ester) and Iab(ester) are produced directly from the compounds of Formulae IXa and IXb, respectively, by treating the latter compounds at temperatures of zero degrees centigrade or slightly lower in a liquid medium, such as an organic solvent, for example, chloroform, methylene chloride, ether, and the like, and in the presence of prototropic agents (proton donating agents) such as water, alcohols, organic acids, and the like, with a mineral acid, such as hydrogen chloride. The reaction mixture can then be washed with successive portions of water and dilute alkali, such as sodium bicarbonate, followed by recovery of the compounds of Formulae Iota(ester) and Iab(ester) by conventional means, such as crystallization, chromatography, or both.

Alternatively, the compounds of Formulae Iaa(ester) and IOLb(6St6I') are obtained by dehydrating the compounds of Formulae Villa and VIIIb, to the compounds of Formulae 15a and 1517, such as 6fi-fluoro-l7B-hydroxy- 4-androsten 3 one and fifl-fluoro-l7/3-hydroxy-4-androstene-3,l1-dione, respectively, and their corresponding 19- nor compounds. The dehydration of the compounds Formulae Villa and W111? is effected in alkali solution or in acidic solution. Suitable acid dehydrating agents include mineral acids, such as, for example, hydrochloric acid and sulfuric acid. Phosphoric acid, acetic acid, p-toluene sulfonic acid, or thionyl chloride in pyridine are also suitable as dehydrating agents. Basic dehydrating agents include, for example, alkali metal and alkaline earth metal hydroxides such as sodium, potassium, barium, and calcium hydroxides, and the like. The thus-obtained compounds of Formulae I/ia and Iflb are then isomerized to the compounds of Formulae Iua and lab, such as 60:- fluoro-17;8-hydroxy-4-androsten-3-one and 6a-flu01'O-17fiasasga-sz hydroxy-4-androstene-3,ll-dione, respectively, and their corresponding l9-nor compounds, in the same manner used to isomerize the compounds of Formulae IBa(ester) andIfib (ester) to the compounds of Formulae Iaa(ester) and Iab(ester), respectively, and esterifying the compounds of Formulae 10661 and 10:17 to the compounds of Formulae Iaa(ester) and Iab(ester). Suitable esterifying agents are those named above in connection with esterifying the compounds'of Formulae VIIIa and VIIIb to the compounds of Formulae IXa and lXb.

Thecompounds of Formulae VIIIa and V IIIb can also be subjected to a simultaneous dehydrationand isomerization treatment to produce the compounds of Formulae Tara and lab in thesame manner disclosed above for the conversion of the compounds of Formulae IXa and IXb to the compounds of Formulae Iua(ester) and Iab(ester).

The compounds of Formulae Ice and load, such as 6afiuoro-4-androstene-3,l7-dione and Gcc-fiLlOIO 4 androstene-3,l1,l7-trione, respectively, and their corresponding l9-nor-compounds, are produced as follows: the compounds of Formulae VIIIa and VIIIb are oxidized, preferably in acetic acid solution, with an oxidizing agent, such as chromic anhydride or sodium dichromate, using a slight excess of the oxidizing agent. At the conclusion of the desired oxidation reaction, the chromic acid oxidant is generally destroyed by addition of methyl alcohol, ethyl alcohol, and the like, and the compounds of Formulae Xa and Xb, such as 6,8-fluoro-u-hydroxyandrostane-3, 17-dione and 6,8-fiuoro-5a-hydroxyandrostane-3,11,17- trione, respectively, and their corresponding l9-nor compounds, can be recovered from the reaction mixture by conventional means. The compounds of Formulae Xa and Xb are then dehydrated to produce the compounds of Formulae 1/30 and Ifld, such as 6(3-fluoro-4-androstene- 3,17-dione and 6fi-fluoro-4-androstene-3,ll,l7-trione, respectively, and their corresponding l9-nor compounds, in the same manner used to dehydrate the compounds of Formulae IXa and IX!) to the compounds of Formulae I Sa(ester) and I,Bb(ester). The compounds of Formulae Life and led are then isomerized to the compounds of Formulae Iac and 106d, in the same manner used to isomerize the compounds of Formulae I,Ba(ester) and 15d (ester) to the compounds of Formulae Iota(ester) and I;3a(ester).

The compounds of Formulae Xa and Xb can also be subjected to a simultaneous dehydration andisomerization treatment to produce the compounds of Formulae lac and load, in the same manner disclosed above forthe conversion of thecompounds of Formulae IXa and IXb, to thecompounds of Formulae Ima(ester) and Iob(St61).

Alternatively, the compounds of Formula Xa can be produced as follows: the compounds of Formula XI, such as 35,17 6-dihydroxy-S-androstene and its corresponding 19'-nor compound, are treated with a peracid, such as peracetic acid or perbenzoic acid to obtain the corresponding.5,6-epoxy compounds represented by Formula XII, such as Sa,6ot-epoxy-3fi,175-dihydroxyandrostane and its corresponding l9-nor compound. The compounds of Formula XII are then treated with hydrofluoric acid, preferably in the presence of an organic solvent, such as methylene chloride, to obtain the compounds of Formula XIII, such as 6fl-fluoro-3B,5ot,17p-trihydroxyandrostane and its corresponding l9-nor compound. The compounds of Formula XIII are oxidized to the compounds of Formula Xa in the same manner used to oxidize the compounds of Formula VIIIa to the compounds of Formula Xa.

' The compounds of Formula Tue, such as 6a-fiuoro-llfihydroxy-4-androstene-3,l7-dione and its corresponding l9-nor compound are produced as follows: the compounds of Formula Iota, such as 6ot-fluoro-4-androstene-3,l1,17- tr-ione or its corresponding l9-nor compound are allowed to react with ethylene glycol, in the presence of a strong acid ascatalyst, to obtain the compounds of Formula.

12 XIV, such as 6-fluoro-5-androstene-3,l1,17-trione 3,17 bis-(ethylene ketal) or its corresponding 19-nor compound, respectively. Suitable strong acid catalysts and other suitable alkane-diols which can be used to form the 3,l7-bis-(alkylene ketals) of the compounds of Formula Ltd, are those acid catalysts and alkanediols mentioned in connection with the conversion of the compounds of Formula Vb to the compounds of Formula VII). The

thus-obtained compounds of Formula XIV are then treated with a reducing agent, for example, a metal hydride, such as lithium aluminum hydride, sodium boro-- hydride, lithium borohydride, and the like, preferably the conditions of the reaction. The thus-obtained compounds of Formula XV are then treated with a hydrolyzing agent, for example, a. dilute aqueous solution of a mineral acid such as sulfuric acid, hydrochloric acid, and the like, preferably, in the presence of an organic solvent such as, for example, methanol, ethanol, dioxane, acetone, and the like, to obtain the compounds of Formula he, such as 6a-fiuoro-l1;8-hydroxy-4-androstene3, l7-dione and its corresponding 19-nor compound. The

hydrolysis reaction can also be effected using organicacids, such as formic acid and acetic acid, or other acidic agents.

The compounds of Formula Ia such as fia-fluoro-llfi, l7,8-dihydroxy-4-androsten-3-one, its corresponding 19- nor compound and the l7-acylates thereof [the compounds of Formula Iaf(ester)] are produced as follows: the compounds of Formula Iozd, such as 6a-fluoro-4- androstene-3,11,17-trione or its corresponding 19-nor compound, are allowed to react with a secondary cyclic alkylene amine, preferably pyrrolidine, in accordance with the procedure disclosed in U. S. Patent 2,781,342, to obtain the compounds of Formula XVI, such as 3-(N- pyrrolidinyl)-6-fluoro-3,S-androstadiene-11,17-dione or its corresponding 19-nor compound, respectively. Other amines which can be used to form the S-enamine derivative are piperidine, C-alkyl substituted piperidines, e. g., 2,4-dimethylpyrrolidine, S-isopropylpyrrolidine, 3,3-dimethylpyrrolidine, and the like, and morpholine, homomorpholine, and the like. The thus-obtained compounds of Formula XVI are then treated with a' reducing agent to obtain the compounds of Formula XVII, such as 3 (N-pyrrolidinyl)-6-fluoro-l lfl,l7B-dihydroxy 3,5 androstadiene or its corresponding l9-nor compound, respec tively. The reduction reaction for the conversion of the compounds of Formula XVI to the compounds of Formula XVII is carried out using the method disclosed for the conversion of the compounds of Formula XIV to the compounds of Formula XV. The thus-obtained compounds of Formula XVII are then hydrolyzed with wa-- ter, aqueous base or acid, alkanols or alkanol water mixtures, to convert them into the compounds of Formula Iaf, such as 6ot-fiuoro-llfl,17,8-dihydroxy-4-androsten-3- one and its corresponding l9-nor compound. The compounds of Formula Iaf are then subjected to treatment with an esterifying agent to obtain the l7-acylates thereof represented by Formula IOLf($t$l'), such as Got-fluoro- 11,8,17fi dihydroxy 4 androsten-3-one l7-acylates and their corresponding 19-nor compounds. Suitable esterifying agents are those named above in connection with esterifying the compounds of Formulae VIIIa and VIllb to the compounds of Formulae IXa and IXb, respectively.

Alternatively, the 1l-oxygenated-6-fluoro compounds of the instant invention, namely the compounds represented by Formulae XIX, Iue, Ia Iotf(ester.), Iab(ester),

2,838,492 7 1'3 lab and load, can be prepared according to'the following ing agent-such as hydrofluoric acid, preferably in the presreaction sequences: ence of an organic solvent, such as methylene chloride, to

1 I. a c=o p i oni I XX' OH: R: I I HO j 0 XVIII Rf 0' CH1 CH 0 O O HO Iozd I Ia o on, r V 7 OH:

OAcyl j I OH IaKester) f 0 I 0:

CH: OH:

OAcyl 0H Iab(ester) Iaib o 0:

wherein R, R and Acyl have the same meaning as preobtain the compounds of FormulaXIX, such as 6B-fluoroviously given. 5u,11fi-dihydroxyandrostane-3,17-dione and its corre- The alternative process for the preparation of the com- 70 sponding 19-nor compound. pounds of Formulae XIX, IaegIocf, Iaf(ester), Iab(ester) The compounds of Formula XIX are then subjected to and lab comprises: treating compounds of the [type simultaneous dehydration and isomerization by treating represented by Formula XVIII such as 5a,6oc-epoxy-11/3- them at temperatures of zero degrees centigrade or slighthydroXy-androstane-3,17-dione 3,17-bis-(ethy1ene ketal) ly lower in a liquid medium, such as an organic solvent, and its corresponding 19-nor compound with a fluorinat- 75 for example, chloroform, methylene chloride, ether, and

the like, and in the presence of prototropic agents (proton donating agents)-such as water, alcohols, organic acids, and the like, with a mineral acid, such as hydrogen chloride. The reaction mixture can then be washed with successive portions of water and dilute alkali, such as sodium bicarbonate, followed by recovery of the. compounds of Formula Iae, such as 6a-fluoro-11fl-hydroxy-4- The compounds of Formula Ia) are recovered by conventional means, such as by chromatography.

The thus-obtained compounds of Formula Iaf are then subjected to treatment with an esterifyingqa'gent to obtain the compounds represented by Formula Iaf(ester), such as 6a-fluoro-1 15,175 dihydroxy 4 androsten-3-one l7- acylates and their corresponding 19-nor compounds. Suitable esterifying agents are organic carboxylic acids, particularly hydrocarbon carboxylic acids (in the presence of an esterification catalyst), containing from one to twelve carbon'atoms, inclusive, or the acid anhydrides and acid halides thereof, such as those specifically mentioned above.

The compounds represented by Formula Iaflester) are then oxidized, preferably in acetic acid solution, with an oxidizing agent, such as chromic anhydride or sodium dichromate, using a slight excess of the oxidizing agent. At the conclusion of the desired oxidation reaction, the chromic acid oxidant is generally destroyed by addition of methyl alcohol, ethyl alcohol, and the like, and the compounds of Formula Iab(ester), such as 6ot-fluoro-l7fihydroxy-4-androstene-3,ll-dione 17-acylates, and their corresponding l9-nor compounds, are recovered by conventional means.

The compounds of Formula Iab(6St1) can be converted to the compounds of Formula Iab, such as 61:- fiuoro-17fl-hydroxy-4-androstene-3,1l-dione and its corresponding l9-nor compound by hydrolysis with a base, such as potassium carbonate, sodium hydroxide, or the like, preferably sodium hydroxide. After the hydrolysis is complete, the reaction mixture is neutralized with an acid, ve. g., acetic acid, and the hydrolyzed product recovered from the reaction mixture by evaporation and crystallization, extraction with methylene chloride, chromatography, and the like, as deemed necessary.

Compound 1016 (where R=methyl), namely, 6oc-fillOIO- ll,8-hydroxy-4-androstene-3,17-dione, can also be obtained by treating Compound XX, 6ot-fiuoro-11fi,17a,21- trihydroxy-4-pregnene-3,ZO-dione, with sodium bismuthate in the presence of an organic solvent, such as acetic acid. The thus-obtained reaction mixture is then treated with an alkali, preferably an alkali metal hydroxide, such as potassium hydroxide, and extracted with an organic solvent such as methylene chloride, or the like, followed by recovery of Compound Iote (where R=methyl) by conventional means, such 'as evaporation and crystallization.

An alternative process for the preparation of thecompounds of Formula load, such as 6a-fiuoro-4-androstene- 3,11,17-trione and its corresponding 19-nor compound comprises: oxidizing the compounds of Formula Iue (obtained by converting the compounds of Formula XV ill into the compounds of Formula XIX and converting the latter compounds into the compounds of Formula lone, as described above and in greater detail below), preferably in acetic acid solution, with an oxidizing agent, such as chromic anhydride or sodium dichromate, preferably the latter. The reaction mixture is diluted with water and the compounds of Formula lad are recovered by conventional means, such as filtration followed by evaporation.

Compound Iocd (where R=methyl), amely, 6a-fiuoro- 4 androstene-3gl1,17-trione, can also be obtained according to the process which comprises: converting Compound XX into Compound IDLE (where R=methyl), as described above and in greater detail below, and treating the thus-obtained Compound law (where R=methyl), as described immediately above and in greater detail below, with an oxidizing agent, such as sodium dichromate, preferably in acetic acid solution, and recovering the product, Compound lad (where R methyl), by conventional means.

This application is a continuation-in-part of application Serial No. 699,505, filed November 29, 1957, now abandoned.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 A. 17p-hydr0xy-5-andr0sten-3-0ne S-ethylene ketal (Compound Vla To thirty grams of 17,8-hydroxy-4-androsten-3-one (testosterone), Compound Va there was added 2.5 grams magnesium sulfate, filtered, and concentrated to dryness.

The dried product was then dissolved in two hundred milliliters of hot methanol, to which there was added twenty milliliters of pyrrolidine to convert unreacted testosterone to its pyrrolidyl enamine. The solution was then concentrated to about 100 milliliters, diluted with methylene chloride, extracted with ice cold 4 N hydrochloride acid and water, the water-soluble testosterone pyrrolidyl enamine hydrochloride formed going into the aqueous layer. The aqueous layer was separated from the methylene chloride layer, and the latter layer was dried over magnesium sulfate, filtered, and concentrated tosdryness. The product, 17o-hydroxyd-androsten-3-one 3-ethylene ketal, Compound VIa so obtained was recrystallized from methanol-ether to which there had been added a few drops of pyridine. The first crop of crystals obtained weighed 7.3 grams, melted at 186 189 degrees centigrade, and had an optical rotation of [a] minus 42 degrees (CHC1 The second crop of crystals obtained weighed one gram and had a melting point of 178-184 degrees centigrade.

B. 5,6-ep0xy-17,8-hydroxyandrostan-3-0ne 3-ethylene ketals (Compounds Vllaa and VIIBa T o a solution of 8.5 grams of the above obtained ketal, Compound Vla in milliliters of chloroform there was added one gram of sodium acetate (anhydrous) and ten milliliters of peracetic acid solution (40 percent) whilst cooling in an ice bath. After standing for two hours, the solution was washed with cold dilute sodium hydroxide and water, dried over magnesium sulfate, filtered, and concentrated to dryness. The a and 5 oxides produced were then separated by chromatography over two hundred grams of synthetic magnesium silicate (Florisil). Elution using 25 O-milliliter fractions containing increasing amounts of acetone in Skellysolve B hexanes gave first the fl-oxide (10 percent acetone) and then the a-oxide (l5 percentacetone). The yields were 3.4 and 4.0 grams, respectively.

Recrystallization of the OL-OXidO (Sofia-epoxy) compound, 5 c,6a-epoxy-17fi-hydroxyandrostan-3-one 3-ethylene ketal, Compound VlIaa from acetone-Skellysolve B hexanes gave a product melting at 205-208 degrees centigrade and 1 having an [ul minus 68 degrees (CHCl I Analysis.-Calcd. for C H O Found; C, 72.32; H, 9.31. Recrystallization of the ,e-oxido (55,6,B-epoxy) compound, 5B;6B-epoxy-17B-hydroxyandrostan-3-one 3-ethylene ketal, Compound vnpa from ether-Skellysolve B hexanes gave aproduct melting at 91-95 degrees centigrade and having an [al minus three degrees (CHCl Analysis.-Calod. for Cal-1 C, 72.38; H, 9.26. Found: C, 72.36; H, 9.76.

C. 613 fluoro 50,17fi dihydroxyandrostan 3 one (Compound VIIla 14.3 grams of the a-oxide, Compound Vllaa was dissolved in 270 milliliters of methylene chloride and cooled to about eight degrees centigrade. 55 milliliters of. 48' percent aqueous hydrofluoric acid were added whilst the reaction mixture was-stirred and cooled in an ice bath. After stirring vigorously for two and one-half hours the reaction mixture was pouredinto 1500 milliliters of ten percent sodium'bicarbonate solution containing ice. The mixture was filtered and thefiltrate separated into an aqueous layer and a methylene chloride layer. The methylene chloride layer was washed with water, dried over sodium sulfate and then evaporated. There was thus obtained 4.4 grams of material which was then redissolved in methylene chloride and adsorbed on 230 grams of Florisil. Elution, using 230-milliliter fractions, was then carried out with a mixture composed of six parts of acetone, thirty parts of Skellysolve B hexanes and 64 parts of methylene chloride, by volume. Fractions to 12 were combined and recrystallized from acetone to give 1.04 grams, of 6B-fluoro-5u,l7,6-dihydroxyandrostan-3-one, Compound VIIIa melting at 253-254 degrees centigrade and having an [ul plus two degrees (acetone).

Analysis.-'Calcd. for C H FO C, 70.34; H, 9.01; F, 5.86. Found: C, 70.44; H, 9.04; F, 5.96.

D. 6B-flnoro-5aJ 7/3-dihydroxyandrostan-3-one 17-pr0- pionate (Compound IXa 0.85 gramof Compound VIIIa were dissolved in three milliliters of pyridine. This solution was then treated with 1.5 milliliters of propionic anhydride and allowed to stand for five hours. The reaction mixture was cooled and nine milliliters of water were addeddrop wise with stirring, causing the precipitation of a solid. After one hour the mixture was filtered and the precipitate dried in vacuo at seventy degrees centigrade to give 1.01 grams of 65-fluoro-5u,17 3-dihydroxyandrostan-3-one 17-propionate, Compound lXa meltingat 234-235 degrees centig rade, j

: Similarly,- by allowing Compound VIIIa to react with the appropriate hydrocarbon carboxylic acids, or the acid anhydrides and acid halides thereof, there are produced .other 17-acylates of 6fl-fiuoro-5a,l7fl-dihydroxyandrostan-3-one such as 6fi-fluoro-5og,17B-dihydroxyandrostan-3-one 17-f0rmate, 6B-fluoro 5a,17B-dihydrox'yandrostan-3-one 17-acetate, 6fi-fluoro-5a,H S-dihydroxyandrostan-3-one 17butyrate, -6;3-fluoro-5u,'17/3-dihydroxyandrostan-S-one 17-valerate, 6;8-fluoro-5a,17fl-dihydroxyandrostan'-; 3 one 17 hexanoate, 6p fluoro 5a,17,8- dihydroxyandrostan-3-one 17 .1aurate, 6B-fluoro-5d,17fidihydroxyandrostan-3-one ,17-trimethylacetate," 6,8-fluoro- 5a,17 3-dihydroxyandrostan-3-one 17-isobutyrate, 6dfluQro-Sa,176-dihydroxyandrostam3one 17-'isovalerate, 16,3 -;fluoro 50,17B dihydroxyandrostan 3 -..one 17- tertiary butylacetate, 6B-fluoro-5u,17fl-dihydroxyandrostan-3-one '17-(fi-cyclopentylpropionate), Gfl-fludro- 5a,17fl dihydroxyandrostan 3 one' 17 cyclohexanecarboxylate, 65 fluoro-5a,17fl-dihydroxyandrostan-3-one 117 cyclohexylacetate, 6B fluoro 5a,17fl dihydroxyfandrostan-S-one 17-benzoate, 6 8-fluoro-5a,17,8-dihydroxy- 18 androstan-3-one 17-phenylacetate, 6B-fluoro-5a,17 3-di hydroxyandrostan-B-one 17-(fl-phenylpropi0nate), 6/3- fluoro- 5oc,17/3 dihydroxyandrostan 3 one 17 (0-, m, p-toluate), 6B-fiuoro-5iz,17fi-dihydroxyandrostan-3r one l7-hemisuccinate, -6fi-fluoro-5a,l7/3-dihydroxyandrostan-3-one 17 hemiadipate, 65 fluoro-5u,17 3-dihy droxyandrostan-3-one 17-acrylate, 6,8-fi1lOIO5oc,17fl-dihydroxyandrostan-3-one 17-crotonate, 6B-fluoro-5a,l7fldihydrdxyandrostan-S-orie 17-undecylenate, 6,6-fluoro- 5a,17 8 dihydroxyandrostan 3 one 17 propiolate, 6 3 fluoro 501,176 dihydroxyandrostan 3 one 17- undecolate, 6,3 fluoro 50:, 175 dihydroxyandrostan 3- one 17-cinnamate, 6 8-fluoro-5a,17B-dihydroxyandrostan- 3-one 17-maleate and 6B-fluoro-5a,Hit-dihydroxyandrostan-3-one17-citraconate.

If the esterifying agent is the free acid, the reaction is carried out in the presence of an esterification catalyst.

If the corresponding acylating agent is solid an inert solvent such as toluene, xylene or dioxane can be added to effect solution and to provide a liquid esterification medium.

nate [Compound Ifla (est;er

One gram of Compound IXa was dissolved in ten milliliters of pyridine and there Wasadded thereto, with stirring, one gram of N-bromoacetamide. The reaction mixture was allowed to stand for thirty minutes, cooled in an ice bath andanhydrous sulfur dioxide was passed over the liquid 'surfaceuntil 1.57 grams were absorbed. The thus obtained reaction mixture was warmed to about 28 degrees centigrade" and maintained at that temperature for one and one-half hours. The reaction mixture was again cooled and there was added dropwise, with'stirring, 28 milliliters -of-a.ten percent sulfuric acid solution'which caused theprecipitation of a solid. The reaction mixture was cooled for two hours at five degrees centigrade. The reaction mixture was filtered and the precipitate obtained was washed with water and dried to give 0.85 gram of product; melting point 112-113 degrees centigrade,

m; 234 mu (log a 4.12)

Recrystallization from a mixture of five milliliters of methanol and one milliliter of water yielded 0.60 gram of -6B-,fluoro-17fi-hydroxy-4-androstan-3-one 17-propio nate Compound I Ba (ester melting at 114-115 degrees centigrate and having an [ocl zero degrees (chloroform). AnalysisJ-Calcd. for C H FO C, 72.89; H, 8.62; F, 5.24. Found: C, 72.86; H, 8.52; F, 5.30.

F. 6ot-fluoro-17B-hydroxy-4-androsten-3-one 17-propionate [Compound Iota (ester Three hundred milligrams of Compound Ipa (ester were dissolved in ten milliliters of reagent grade chloroform (containing traces of alcohol) and the solution cooled in an ice-salt bath. Anhydrous hydrogen chloride was bubbled into the cold solution for twenty minutes, followed by nitrogen for fifteenminutes. The solution was washed with water and there was thus obtained an aqueous and organic layer. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 268' milligrams of residue. The residue was their crystallized from three milliliters of eighty percent methanol to yield milligrams of 6a-fluoro-17p-hydroxy-4-androsten-3-one 17-propionate, Compound laa (ester melting at 108-110 degrees centigrade and having an [ab plus 79 degrees (chloroform).

' The infrared absorption (Nujol mull) exhibited bands at 1730 (ester), 1663 (c p-unsaturated ketone), and 1620 cm-. (double bond).

G. 6B-fluoro-176-h)droxy-4-androsten-3-one (Compound 1 1) 7 Following the procedure of Example 1, Parts A through means 19 a C, there is obtained Compound VIIIa A solution containing eleven grams of Compound VIIIa in 350 milliliterssof absolute ethyl alcohol is cooled to fifteen degrees centigrade and forty milliliters of 0.1 N sodium hydroxide is added thereto. The solution thus-obtained is cooled to about eight degrees centigrade, and after being allowed to stand at that temperature for approximately 24 hours, treated with four milliliters of acetic acid and concentrated to a residue which is extracted with methylene chloride. The methylene chloride extract is washed with Water, dried over sodium sulfate, concentrated to about 100 milliliters and chromatographed over 400 grams of Florisil (synthetic magnesium silicate). The chromatographic column is eluted in ZOO-milliliter fractions with Skellysolve B hexanes containing increasing proportions of acetone, starting with five percent acetone in Skellysolve B hexanes. Those fractions exhibiting an ultra-violet maximum at are combined and recrystallized from acetone-Skellysolve B hexanes to give crystals of 6fi-fluoro-l7B-hydroxy-4- androsten-3-one, Compound lfia A stoichiometric equivalent amount of Compound Tim, is substituted for Compound Ifia (ester in the procedure of Example 1, Part F, to obtain 6u-fiuoro-17/3- hydroxy-4-androsten-3-one, Compound ID601- A stoichiometric equivalent amount of Compound Iaa is substituted for Compound VIIIa in the procedure of Example 1, Part D, to obtain 6a-fiuoro-17,8-hydroxy-4-androsten-3- one 17-propionate, Compound Iaa (ester EXAMPLE 2 6ot-fluoro 17/3 hydroxy 4 tandrosten 3 one 17 propionate [Compound Iaa (ester directly from 6/3- fluoro 505175 dihydroxyandrostan 3 one 17 propionate (Compound IXa 1 I Theprocedure described in Example 1, Parts A through D, was followed to produce Compound IXa 300 milligrams of which is dissolved in 25 milliliters of chloroform and cooled to minus ten degrees centigrade. Anhydrous hydrogen chloride gas is then bubbled through the cold solution for several hours. The reaction mixture is washed with water, five percent sodium bicarbonate solution and again with water. The chloroform reaction mixture remaining after the final washing is dried over sodium sulfate and evaporated. The residue remaining is recrystallized from methanol to give 6u-fluoro-l7/3- hydroxy 4 androsten 3 one 17 propionate, Compound Iaa (ester Following the procedure of Example 1, Parts A through C, there is obtained Compound VIIIa A stoichiometric equivalent amount of Compound VIlIa is substituted for Compound lXa in the procedure described immediately above to produce 6a-fluoro-l7fi-hydroxy-4-androten-3-one, Compound 11m The latter compound can then be esterified to Compound Iau (ester by following the procedure of Example 1, Part D, substituting a stoichiometric equivalent amount of Compound Iaa for Compound V1IIa EXAMPLE 3 A. 17fi-hydroxy-5-androstene-3,11-dione 3-ethylene keta'l (Compound Vlb A stoichiometric equivalent amount of l7p-hydroxy- 5-androstene-3,1 l-dione (1 l-ketotestosterone), Compound Vb is substituted for Compound Va in the procedure of Example 1, Part A, to obtain 17 3-hydroxy-5- andrstene-3,ll-dione 3-ethylene ketal, Compound VIb B. 5,6-epoxy-I7fl-hydroxyandrostane-3JJ-dione 3-ethylene ketals (Compound VIIab and Vllflb A stoichiometric equivalent amount of Compound VIb is substituted for Compound V10 in the procedure of Example 1, Part B, to obtain a,6o-epoxy'-17fl-hydroxy androstane-3,1l-dione 3-ethylene ketal, Compound Vllab and 5,8,6p-epoxy-1713-hydroxyandrostane-3,l1- dione 3-ethy1ene ketal, Compound VII 317 which can be separated as described in Example 1, Part B, i. e., chromatography on Florisil followed by elution with Skellysolve B hexanes containing increasing proportions of acetones.

C. 613 fluoro 511,171? dihydroxyandrostane 3,11-

dione (Compound VIIIb A stoichiometric equivalent amount of Compound Vllub is substituted for Compound VTIOtd in the procedure of Example 1, Part C, to obtain 6fi-fluoro-5a,l7fidihydroxyandrostane-3,ll-dione, Compound VlIIb a crystalline solid.

D. 65 fluoro 50:,175 dihydroxyandrostane 3,11-

dione 17-pr0pionate (Compound lXb A stoichiometric equivalent. amount of Compound VIIIb is substituted for Compound VlIIa in the procedure of Example 1, Part D, to obtain crystals of 6pfiuoro 50:,i7fi dihydroxyandrostane 3,11 dione l7- propionate, Compound 1X11 Similarly, by allowing Compound VlIlb to react with the appropriate hydrocarbon carboxylic acids (in the presence of an esterification catalyst), or the acid anhydrides and acid halides thereof, such as those named above, there are produced other l7-acylates of 6/8-fluoro- 5a,17fi-dihydroxyandrostane-3,ll-dione, as, for example, the 17-acetate, the l7-hemisuccinate, and the l7-benzoate.

E. 65 fluoro 17,6 hydroxy 4 androstene 3,11-

dione 17-propionate [Compound I,8 (ester A stoichiometric equivalent amount of Compound IXb is substituted for Compound IXa in the procedure of Example 1, Part E, to obtain 6fi-fluoro-17fi-hydroxy- 4 .androstene 3,11 dione l7 propionate, Compound Ifibflesten).

F. 60: fluoro 17/8 hydroxy 4 androstene 3,11-

dione 17-propionate [Compound Iab (ester A stoichiometric equivalent amount of Compound I/3b (es ter is substituted for Compound I 8a (ester in the procedure of Example 1, Part F, to obtain oer-fluoro- 17fi-hydroxy-4-androstene-3,1l-dione 17-propionate, Compound Ieb (ester a crystalline solid.

Following the procedure of Example 1, Parts A through C, using Compound Vb as the starting material, there is obtained Compound V11Ib A stoichiometric equivalent amount of Compound VIIIb is substituted for Compound VI'II4 in the procedure of Example 1, Part G, to obtain '6;3-fiuoro-l7B-hydroxy-4 androstene 3,11 dione, Compound IBb A stoichiometric equivalent amount of Compound Iflb is substituted for Compound I/iaflesteq) in the procedure of Example 1, Part F, to obtain 6a-fluoro- '17,8-hydroxy-4-androstene-3,1l-dione, Compound 10:17 A stoichiometric equivalent amount of Compound Iocb is substituted for Compound VIIIa in the procedure of Example 1, Part D, to obtain 6a-fluoro-l7B-hydroxy-4- androstene-3,11-dione 17-propionate, Compound Iub (ester EXAMPLE 4 6oz fluor o 17p hydroxy 4 androstene 3,11 dione 17-propionate [Compound 1ab (ester directly from 65 fluoro 5a,17}3 dihydroxyandrostane 3,11 dione 17-propi0nate (Compound lXb 'hydroxy-4-androstene-3,1I-dione, Compound Iub 21 the procedure of Example 2 to produce 6a-fluoro-17fl- The latter'compound can then be esterified to Compound Idb (ester by following the procedure of Example 1, Part D, substituting a stoichiometric equivalent amount of Compound Iocb for Compound VHIa EXAMPLE A. 17/3 hydroxy 19 nor -5 androsten 3 one 3- ethylene ketal (Compound Vla A stoichiometric equivalent amount of 17,8-hydroxyl9-nor-4-androsten-3 one (19 nortestosterone), Compound Va is substituted for Compound Va in the procedure of Example 1, Part A, to obtain 17p-hydroxy-19- nor-5-androsten-3-one 3-ethylene ketal, Compound Vin B. 5,6 epoxy 17/3 hydroxy 19 norandrosten 3 one 3 ethylene ketals (Compounds Vllaa and VIIfiaz) A stoichiometric equivalent amount of Compound VIa is substituted for Compound VIa in the procedure of Example 1, Part B, to obtain 5a,6u-epoxy-17p-hydroxy- 19-norandrostan -.3 one 3 ethylene ketal, Compound Vllaa and 5fl,6Bepoxy-17p-hydroxy 19 norandrostan- 3-one 3-ethyleneketal, Compound Vllfia which can be separated as described in Example 1, Part B.

C. 6,6 fluoro 511,175 dihydroxy 19 n0randrostan-3-' one (Compound V1IIa A stoichiometric equivalent amount of Compound VIIaa is substituted for Compound VIIaa in the procedure of Example 1, Part C, to obtain 6;3-fluoro-5a,17pdihydroxy-19-norandrostan-3-one, Compound VIIIa D. 6 8 fluoro 50;,175 dihydroxy 19 norandrostan-3- one-17-propionate (Compound IXa A stoichiometric equivalent amount of Compound VIIIa2 is substituted for Compound VIIIa in the pro- 'cedure of Example 1, Part D, to obtain 6j3-flu0r0-5oz,17,8-

. dihydroxy-19-norandrostan-3 one 17 propionate, Compound IXa E. 6,8 fluoro 17 3 hydroxy 19 nor 4 androsten 3- one 17 propionate [Compound lfla (ester A stoichiometric equivalent amount of Compound IXa is substituted for Compound IXa in the procedure of Example 1, Part E, to obtain 6p-fluoro-l'7i3-hydroxy-l9- nor-4-androsten-3-one l7-propionate, Compound Ipa (ester F. 6d fluoro 17,8 hydroxy 19 nor 4 androsten- 3 one 17 propionate [Compound I0dl (EStr A stoichiometric equivalent amount of Compound Ifla (ester is substituted for Compound lfiaflester in procedure of Example 1, Part F, to obtain 6a-fluoro-17phydroxy-l9-nor-4-androsten-3-one l7-propionate, Compound Iaaz(ester a crystalline solid.

Following the procedure of Example 1, Parts A through C, using Compound Va; as the starting material, there is obtained Compound VIIIa A stoichiometric equivalent amount of Compound VIIIo is substituted for Compound VIIIa in the procedure of Example 1, Part G, to obtain 65 fluoro 17 8 hydroxy 19 nor 4 androsten-3-one, Compound Ifia A stoichiometric equivalent amount of Compound Ifia is substituted for Compound Ifia (ester in the procedure of Example 1, Part F, to obtain 60: fluoro 17,3 hydroxy 19 nor 4 androsten- 3-one, Compound ldaz-l A stoichiometric equivalent amount of Compound Iota: is substituted for Compound 22 VIIIa in the procedure of Example 1, Part D, to obtain 6:1 fluoro 17p hydroxy 19 nor 4 androsten 31- one 17 propionate, Compound Iota-2(ester EXAMPLE 6 60a fluoro 17,8 hydroxy 19 nor 4 androsten 3- one 17 propionate [Compound 1aa (ester directly from 65 fluoro 50:,17/3 dihydroxy 19 norandrostan 3 one 17 propionate (Compound lXa A stoichiometric equivalent amount of Compound IXa is substituted for Compound IXa in the procedure of Example 2 to obtain 6u-fiuoro-17,3-hydroxy-l9-nor-4- androsten-B-one 17-propionate, Compound Iua (ester The procedure of Example 1, Parts A through C, is followed, substituting a stoichiometric equivalent amount of Compound Va for Compound Va to obtain Compound VIIIa A stoichiometric equivalent amount of Compound VIIIa is substituted for Compound IXa in the procedure of Example 2 to produce 60c-fll10l'O-17B- hydroxy-l9-nor-4-androsten-3-one, Compound Iaaz. The latter compound can then be esterified to Compound Iaa (ester by following the procedure of Example '1, Part D, substituting a stoichiometric equivalent amount of Compound Iaa for Compound VIIIa EXAMPLE 7 A. 1 7p-hydroxy-1 9-nor-5-androstene-3J1-dione ene ketal (Compound Vlb A stoichiometric equivalent amount of l7B-hydroxy-19- nor-5 -andr0stene-3,l l-dione (1 l-keto-19-nortestosterone), Compound Vb disclosed in U. S. Patent 2,781,368, is substituted for Compound Va in the procedure of Example I, Part A, to obtain l7 8-hydroxy-l9-nor-5-androstene-3,1l-dione 3-ethylene ketal, Compound VIb B. 5,6-epoxy-17,8-hydr0xy-1Q-norandrostane 3,11 dione 3-ethylene kemis (Compounds Vllozb and VII/812 A stoichiometric equivalent amount of Compound VIb is substituted for Compound VIa in the procedure of Example 1,-Part B, to obtain 5a,6a-epoxy-l7/3-hydroxyl9-norandrostane-3,ll-dione S-ethylene ketal, Compound Vllab and 53,6/3-epoxy-17,8-hydroxy-l9-norandrostane- 3,1l-dione 3-ethylene ketal, Compound VIIBb which can be separated as described in Example 1, Part B, i. e., chromatography on Florisil followed by elution with Skellysolve l3 hexanes containing increasing proportions of acetone.

C. Gfl-fluoro-SaJ 7/3-dihydroxy-19 norandrostane 3,11-

dione (Compound VIIIb 1 D. 6p-fluoro-5a,17fl-dihydroxy-19 norandrostane 3,11

dione 17-pr0pi0nate (Compound IXb 3-ethyl- A stoichiometric equivalent amount of Compound VIIIb is substituted for Compound VIIIa in the procedure of Example 1, Part D, to obtain 6B-fluoro-5u,17p-di- E. 6fi-flu0ro-17 8-hydroxy-19-n0r-4 androstene 3,11- dione 17-propionate [Compound IBb (ester A stoichiometric equivalent amount of Compound IXbg sa -Sana F. 6u-flu0ro-17fl-hydr0xy-19-nor-4 androstene 3,11- dione 17*pro-pi0nate [Compound Ial2 (ester A stoichiometric equivalent amount of Compound Ib (est'er is substituted for Compound Ifla (ester in the procedure of Example 1, Part F, to obtain 6tx-fillOI'O- -l'7fl-hydrox'yl9-nor-4-androstene-3 ,1 l-dione 17-propionate, Compound Iub (ester a crystalline solid.

Following the procedure of Example 1, Parts A through C, using Compound Vb as the starting material, there is obtained Compound VIlI b A stoichiometric equivalent amount of Compound VIIIb is substituted for Compound VIHa in the procedure of Example 1, Part G, to obtain ofi-fiuoro l m-hydroxy-l9-nor-4-androstenc-3,11 dione, Compound Ifibg. A stoichiometric equivalent amount of Compound Ifib is substituted for Compound Ipa (ester in the procedure of Example 1, Part F, to obtain 6afluor o-l7/3-hydroxy-l9-nor-4-androstene-3,l l-dione, Compound ICCbz. A stoichiometric equivalent amount of Compound Iab is substituted for Compound VIIIa in the procedure of Example 1, Part D, to obtain 6ot-fluoro- 17f3-hydroxy-l9-nor-4-androstene-3,1 l-dione 17-propionate, Compound labflester EXAMPLE 8 6 a-fluor'o-l 7B-hydroxy-1'9-nor-4-androstene-3J1-dione 1 7- propionwze [Compound Iab (ester directly from 6fi-fluoro-5tt,17 8-dihydroxy-19 norandrostane 3,11-

dione 17-propionate (Compound lXb A stoichiometric equivalent amount of Compound IXbg is Substituted for Compound IXa in the procedure of Example 2 to obtain 6u-fluoro-l7fl-hydr0xy-19-nor-4- androstene-3,1l-dione 17-propionate, Compound Iotb (ester I The procedure of Example 1, Parts A through C, is followed, substituting a stoichiometric equivalent amount of Compound Vb for Compound Va to obtain Compound VIIIb A stoichiometric equivalent amount of Compound Vlllb is substituted for Compound 1X11, in the procedure of Example 2, to produce 6tx-fluoro-l7phydroxy-l9-nor-4-androstene-3,l l-dione, Compound Iotb The latter compound can then be esterified to Compound IocbflfiStCfi) by following the procedure of Examplc 1, Part D, substituting a stoichiometric equivalent amount of Compound Iab for Compound Villa,-

EXAMPLE 9 A. fi-fluoro-Sodhydroxyandrostane-3,I7 dione (Compound Xa To an ice-bath-cooled solution of three grams of chromic anhydride, 130 milliliters of acetic acid and three milliliters of water, there is added, whilst stirring and cooling, four grams of 6p-fluoro-5a,17fi-dihydroxyandrostan-3-one, Compound VIIIa obtained by the procedures of Example 1, Parts A through C. After standing for approximately fifteen minutes, the reaction mixture is warmed to about 25 degrees centigrade and allowed to stand for several hours. To the reaction mixture there is then added elevent milliliters of methyl alcohol and 300 milliliters of water, the addition of the latter causing a solid to precipitate. The precipitate is collected and washed with water to give 2.5 grams of crude product. Recrystallization from acetonelifillYSOlVfi B hexanes yields 6,8-fluoro-a-hydroxyandrostane-3,l7-dione, Compound Xa a crystalline solid.

Alternatively, Compound Xa; is prepared by epoxidizing 3/3,17;3-dihydroxy-5-androstene, Compound Xla with peracetic acid to produce 5t .,6u-epoxy-3[3,17,8-dihydroxyandrostane, Compound XIIa The treatment of Compound XIIa; with anhydrous hydrogen fluoride in the presence of an anhydrous organic solvent, preferably a mixture of chloroform and tetrahydrofuran, is productive of 6B-fiuoro-3/3,5u,l7B-trihydroxyandrostane, Compound XIIIa The latter. compound is then oxidized with chromic anhydride to produce 6fi-fiuoro-5'a-hydroxyandrostane-3,l7-dione, Compound Xa B. 6o-fluoro-4-androstene-3,17-di0ne (Compound C. 6ot-flttoro-4-androstene-3,17-dione (Compound Inc A stoichiometric equivalent amount of Compound Ific is substituted for Compound Iflaflester) in the procedure of Example 1, Part F, namely, bubbling anhydrous hydrogen chloride into a solution of Compound Inc, in chloroform, to prepare 6o; fluoro 4 androstene 3,17- dione, Compound Iac isolated as a crystalline solid.

EXAMPLE 10 6a fluoro 4 androstene 3,17 dz'one (Compound Inc directly from dfl-fluoro 5 0t hydroxyandrostane- 3,17-dione (Compound Xa A stoichiometric equivalent amount of Compound Xa is substituted for Compound IXa in the procedure of Example 2 to obtain 6a-fluoro'4-andr0stene-3,l7-dione, Compound Iac directly.

EXAMPLE 11 A. 6,8 fluoro 50c hydroxyandrostaue 3,11,17

' (Compound Xb A stoichiometric equivalent amount of Compound VHIb is substituted for Compound VIIIa; in the procedure of Example 9, Part A, to obtain 6B-fluoro-5a-hydroxyandrostane-3,1 1,17-trione, Compound Xbi.

B. 6;? fluoro 4 androstene 3,11,17 trione' (Compound fi z) A stoichiometric equivalent amount of Compound Xb is substituted for Compound IXa in the procedure of Example 1, Part E, to obtain 6;3-fiuoro-4-androstene 3,11,17-trione, Compound Ifld C. 6a fluoro 4 androstene 3,11,17 trione (Compound Iotd trione A stoichiometric equivalent amount of Compound Ifid is substituted for compoundIfiaflester in the procedure of Example 1, Part E, to obtain 6a-fluoro-4-androstene- 3,11,17-trione, Compound latch, a crystalline solid product.

EXAMPLE 12 6a fluoro 4 androstene 3,11,17 trione (Compound 10rd,) directly from 6;? fluoro 5a hydroxyandrostane-3,1I,17-trione (Compound X11 ,7

A stoichiometric equivalent amount of Compound Xb is substituted for Compound IXa in the procedure of Example 2 to obtain 6a-fluoro-4-androstene-3,11,l7-tri' one, Compound Iad directly.

EXAMPLE 13 A. 6/3 fluoro 5oz. hydroxy 19 norandl'ostan 3,17- dione (Compound Xa A stoichiometric equivalent amount of Compound VIIClg is substituted for Compound VIIIa in the procedure of Example 9, Part A, to obtain 6,3-fiuor0-5a-hydroxy-l9-norandrostane-3,17-dione, Compound X12 Alternatively, Compound Xa is prepared by epoxidizling 35,175 dihydroxy 19 nor 5 androstene, Compound Xla [Hartman, J. A. C. 8., vol. 77, p. 5151-5 4 2.5 (1955) ,notingiparticularlyp. 5153], with .peracetio acid to produce a,6a epoxy 3,8,175 dihydroxy 19 norandrostane, Compound XIIa The treatment of Compound XIIa with anhydrous hydrogen fluoride in the presence of an anhydrous organic solvent, preferably a mixture of chloroform and tetrahydrofuran, is productive of 6p fiuoro 3,651,175 trihydroxy 19 norandrostane, Compound XIIIHE. The latter compound is then oxidized with chromic anhydride to produce 6,8-fluoro- 5a: hydroxy 4 19 norandrostane 3,17"- dione, Compound Xa B. 6/3 fluoro 19 nor 4 nndrostene 3,17 dione (Compound 1,80

A stoichiometric equivalent amount of Compound Xa,

. is substituted for Compound IXa in the procedure of Example 1, Part E, to obtain 6,6-fiuoro-l9-nor4androstene-3,l7-dione, Compound I Sa C. 6a fluoro 19 nor 4 androstene 3,17 dion (Compound 1046 A stoichiometric equivalent amount of Compound I50 is substituted for Compound IBa (ester in the procedure of Example 1, Part F, to obtain crystals of 6afluoro-l9-nor-4-androstene-3,17-dione, Compound Iac A stoichiometric equivalent amount of Compound Xa is substituted for Compound IXa in the procedure of Example 2 to obtain 6a-flu-oro-19-nor-4-androstene-3,l7- dione, Compound Iondirectly.

EXAMPLE l5 I v 50c hydroxy 19 norandrostane 3,11, 17-trione (Compound Xb a A stoichiometric equivalent amount of Compound VIIIbis substituted for Compound VIIIa in the procedure of Example 9, Part A, to obtain 6p-fluoro-5a-hydroxy-19-norandrostane-3,11,17-trione, Compound Xbz- B. 6;? fluoro -19 nor 4 androstene 3,11,17 trione (Compoundlfid A. 65 fluoro A stoichiometric equivalent amount of Compound Xb sp sm.

is substituted for Compound IXa in the procedure of I Example 1,. Part E, to obtain 6B-fluoro-l9-nor-4-androstene-3,1l,l7-trione, Compound lfia C. 60: fluoro 19 nor 4 androstene 3,11,17 trione (Compound lad A stoichiometric equivalent amount of Compound 113d; is substituted for Compound Ipa (ester in the procedure of Example 1, Part F, to obtain 6a-fluoro-19-nor- 4-androstene-3,11,17-trione (Compound la'd a crystalline solid.

. EXAMPLE 16 6a fluoro l9 nor 4 androstene 3,11,17 trione (Compound Iocd directly from 6ot-fluoro-5a-hydroxy- 19-norandrostune-3J1,17-trione (Compound X b A stoichiometric equivalent amount of Compound Xb issubstituted for Compound IXa in the procedure of Example 2 to obtain 6a-fluoro-19-nor-4-androstene-3,11, 17-trione, Compound Iad f EXAMPLE 17. i

A. 6 flu0r0-5-andr0stene-3J1,17+trione 3,17-bis-(ethylene ketal) (Compound XIV move ,water of reaction, for approximately 7.5..l1our's', The thus-obtained reaction mixture is cooled, washed with water, ten percent aqueous potassium bicarbonate solution and again with water. The washed benzene layer obtained, following the second water washing, is separated and dried over sodium sulfate. The solvent is removed from the benzene solution by distillation and the residueremaining is recrystallized from aqueous acetone containing'five drops of pyridine to give 6fluoro-5-androstene-3,11.l7-trione 3,l7-bis-(ethylene ketal), Compound X[V B. 6 fluoro 1Ifi-hydi'oxy-S-androstene-3,17-di0ne 3-17- bis-(ethylene ketal) (Compound X V water. The thus-obtained mixture is then thoroughly ex-- tracted with ether. The ether extract is washed with.- water, dried over sodium sulfate, and distilled to give a. residue of crude 6-fluoro-1lfi-hydroxy-5-androstene-3,17 dione 3,17-bis-(ethylene ketal), Compound XV C. 60: flu oro 11,8 hydroxy 4 androstene 3,17'-

. dione (Compound Iue To the crude residue of Compound XV there is added forty milliliters of acetic acid and fifteen milliliters of water. The reaction mixture is warmed on a steam batlr at approximately 95 degrees centigrade for about 45 minutes, cooled to room temperature and poured onto 150/ grams of ice, with stirring until the ice melts. The re-,

action'rnixture is carefully treated portionwise with thirty grams of solid sodium bicarbonate, whilst continuously stirring. The mixture thus-obtained. is extracted with methylene chloride. The methylene chloride extract is washed with water, dried over sodium sulfate and chromatographed over 300 grams of synthetic magnesium silicate (Florisil), followed by elution using IUD-milliliter fractions of Skellysolve B hcxanes plus increasing proportions of acetone from one to fifty percent. The fractions are subjected to infrared analyses and those fractions which show bands for hydroxyl and 3,17-carbonyl groups are combined and crystallized from an acetone-v hexane mixture to give crystals of du-fluoro-llp-hydroxy- 4-androstene-3,17-dione, Compound Iae EXAMPLE 18 A. 6 fluoro-I 9-nor-5 -andr0sten -3,1 1,1 7 tri0ne 3,17-bis- (ethylene ketal) (Compound XIV B. 6 fluoro 11,8 hydroxy 19 nor 5 androstene 3,17-dione 3,17-bis-(ethylene ketal) (Compound X V A stoichiometric equivalent amount of Compound XIV is substituted for Compound XIV, in the procedure of Example 17, Part B, to obtain a crude residue of 6- fluoro-l1,8-hydroxy-19-nor-5-androstene-3,17-dione 3,17-

, bis-(ethylene ketal), Compound XV C. 6st fluoro 11,8 hydroxy 19 nor 4 androstene 3,17-aiom2 (Compound 10:2

The crude residue of Compound XV is substituted for the crude residue of Compound XV in the procedure of Example 17, Part C, to obtain 6a-fluoro-11 S-hydroxyl 9-nor-4 -androstene-3,17-dione, Compound Ine a crystalline solid.

EXAMPLE 19 A. 3 (N pyrrolidinyl)'- 6- fluoro 3,5 androstadiene-1l,17-dione (Compound X V1 A mixture of 3.18 grams of 6a-fluoro-4-androstene- 3,11,17-trione, Compound 1nd,, and thirty milliliters of methyl alcohol is heated to approximately the boiling point, cooled slightly and treated with 0.78 gram of pyrrolidine. Upon stirring the reaction mixture gently and allowing it to cool to room temperature a solid material separates. The entire reaction mixture is refrigerated at approximately zero degrees centigrade for several hours and the precipitated material is isolated by filtration, washed with methyl alcohol, and dried to yield 3-(N- pyrrolidinyl) 6 fluoro 3,5 androstadiene 11,17 dione, Compound XVI B. 3 (N pyrrolidinyl) 6 fluoro 1113,1713 dillydroxy-3,S-androstadiene (Compound XVII A solution of two grams of Compound XVI in ninety milliliters of anhydrous tetrahydrofuran is added, over approximately a five minute period, whilst stirring under nitrogen, to a mixture of one gram of lithium aluminum hydride and sixty milliliters of anhydrous diethyl ether. The reaction mixture is stirred at room temperature for approximately fifteen minutes, followed by the cautious addition of twelve milliliters of water. The thus-obtained reaction mixture is then thoroughly extracted with ether. The ether extract is washed with water, and dried over sodium sulfate. The solvent (ether) is then removed at room temperature under reduced pressure to give a crude residue of 3-(N-pyrrolidinyl)-6-fiuoro-11,8,175-dihydroxy-3,S-androstadiene, Compound XVII C. 6 1, fluoro 113,175 dihydroxy 4 androsten 3 one (Compound Iaf The crude residue of Compound XVII isheated at reflux for several hours in a buffered acetate solution of 2.5 grams of sodium acetate, eight milliliters of water, 2.5 milliliters of acetic acid and fifty milliliters of methyl alcohol; Upon dilution with water and cooling, a solid material separates. The solid material is isolated and recrystallized from an acetone-hexane mixture to give crystals of 601-111101-11,8,l.7fi-dlllydIOXY-4-8T1d1'0516I1-3- one, Compound laf D. 6;: fluoro 11fi,l. /3 dihydroxy 4 androsfen 3- one 17-propionate [Compound Iuf (esler A mixture of 0.3 gram of Compound Inf, in two milliliters of dry pyridine is cooled to approximately fifteen degrees centigrade and treated with 1.5 milliliters of propionic anhydride. The reaction mixture is allowed to stand at approximately 25 degrees centigrade for about eight hours and then is poured into forty milliliters-of water vand stirred for five hours with the formation of a solid material. The solid material is isolated, Washed with water, dried, and recrystallized from an ether-hexane mixture to give crystals of 6u-fluoro-115,175-dihydroxy- 4-androsten-3-one 17-propionate, Compound Iuf (ester Similarly, by reacting Compound Inf, with the appropriate hydrocarbon carboxylic acids (in the presence of an esterification catalyst), or the acid anhydrides and acid halides thereof, such as those named above, there are produced other 17-acylates of 6u-fluoro-11B,17B-dihydroxy-4-androsten-3-one as, for example, the 17-acetate, the 17-hemisuccinate,.and the 17-benzoate.

. EXAMPLE 20 A. 3 (N pyrrolidinyl) 6 fluoro 19 nor 3,5 androstadiene-1L17-dior ze (Com-pound X VI "A stoichiometric equivalent amount of 6u-fiuoro-19- nor-4-androstene-3,11,17-trione, Compound lad is sub- 28 stituted; for Compound lad; in the procedure of Example 19, Part A, to obtain 3-(N-pyrrolidinyl)-6-tluoro-19-nor- 3,5-androstadiene-11,17-dione, Compound XVI B. 3 (N Q pyrrolidinyl) 6 fluoro 115,176 dihydroxy- 19-nor-3,S-androstadiene (Compound X VII A- stoichiometric equivalent amount of Compound XVI- is substituted for Compound XVI in the procedure of Example 19, Part B, to obtain a crude residue of 3 (N- pyrrolidinyl) '6 fiuoro 1118,1713 dihydroxy- 10-nor-3,5-androstadienc, Compound XVII C. 60c fluoro 1113,17 9 dihydroxy 19 nor 4 androsten-3-one (Compound laf The crude residue of Compound 'XVII is substituted for the crude residue of Compound XVII in the procedure of Example 19, Part C, to obtain 6u-fluoro-11p,l7;3- dihydroxy-l9-nor-4-androsten-3-one, Compound 10%.

D. 60: fluoro 115,17/8 dihydroxy 19 nor 4 androsten-3-one 17-propi0nate [Compound Iotf (ester A stoichiometric equivalent amount of Compound IOLf issubstituted for Compound Inf, in the procedure disclosed'in'Example 1, Part D, toobtain 6u-fluor'o-11/3, 17fl dihydroxy-19-nor-4-androsten-3-one 17-propionate, Compound Iixf (ester Similarly, by. reacting Compound Iaf with the appropriate hydrocarbon carboxylic acids (in the presence of an esterification catalyst), or the acid anhydrides and acid halides thereof, such as those named above, there are produced other 17-acylates of 6u-fluoro-11d17fl-dihydroxy-l9-nor-4+androsten-3-one.

EXAMPLE 21 A. 6;? fluoro 50:,11/8 dihydroxytrndrostane 3,17 dione (Compound XIX Three grams of 5u,6u-epoxy-11fi-hydroxyandrostane-3, 17-dione 3,17-bis-(ethylene ketal), Compound XV1II (preparedlaccording to the procedure disclosed'in copendingapplication Serial No. 661,626, filed May 27, 1957) in-25 milliliters of methylene chloride contained in a polyethylene bottle is treated with nine milliliters of 48 percent hydrofluoric acid. The reaction mixture thusobtained is stirred at room temperature for several hours and then cautiously poured into a mixture of 45 milliliters of methylene chloride andfifty milliliters of ice cold 1.5 molar aqueoussodium carbonate solution and stirred with caution. Upon standing the mixture separates into an aqueous and a methylene chloride layer. The layers are separated and themethylene chloride-layer is washed with water and dried, over sodium sulfate. Evaporation of the methylene chloride gives a residue which contains 6fi-fluoro-5a,11fi-dihydroxyandrostane-3,17 dionc, Compound XIX B. 60cfluoro 11/3 hydroxy 4 androstene 3,17 dione (Compound Iae The residue, containing Compound XIX produced in Example 21, Part A, above, is dissolved in 200 milliliters of chloroform and seven milliliters of ethyl alcohol and treated with anhydrous hydrogen chloride gas, whilst maintaining the temperature at approximately from minus five to minus ten degrees centigrade. The solution thus-obtained is washed with successive portions of water, aqueous sodium bicarbonate solution and water, dried over sodium sulfate, concentrated to 35 milliliters and chromatographed over 75 grams of activated alumina. Thechromatographic column is eluted with Skellysolvc B hexanes plusincreasing proportions of acetone from two to fifty percent and collected in fifty-milliliters fractions.- Fractions 8 through 19 are combined and the solvent-removed by-evaporation leaving a residue. The residue is recrystallized from methylene chloride-hexane to give- 60: fiuoro 11/3 hydroxy 4 androstene 3,17- dione, Compound 10:6 a crystalline solid.

afi ag a 115,175 dihydroxy 4 androsten 3- one (Compound lotf "'A'mixture of 200 milligrams of Compound Iae and fifty milliliters of methyl alcohol is cooled to approximately zero degrees centigrade and treated with 22.4 milligrams (1.5 moles) of analytically pure sodium borohydride. The reaction mixture is allowed to stand at about zero degrees centigrade for approximately one hour, acidified with two drops of acetic acid and taken to dryness in vacuo. The residue is triturated thoroughly with methylene chloride and the solution thus-obtained washed with water, dried over sodium sulfate, concentrated to thirteen milliliters and chromatographed over ten grains of activated alumina. The chromatographic column is eluted with benzene plus increasing proportions of acetone fromfour to fifty percent and collected in five-milliliter fractions. The solvent is removed from each fraction and the residue obtained from each fraction is subjected to infrared analysis. Those residues which show the characteristic bands for the 3-keto-A -system and no band for the C carbonyl group are combined and recrystallized from chloroform-Skellysolve C heptanes to give crystals of 6a-fluoro-115,175-dihydroxy-4- androsten-S-one, Compound Iaf D. 60: fluoro 115,175 dihydroxy 4 androsten-S-one 17-acetate [Compound Iotf (eszer .A mixture of 0.30 gram of Compound Iaf in two milliliters of pyridine is cooled and treated with 1.5 milliliters of acetic anhydride. The reaction mixture is allowed to stand at 25 degrees centigrade for approximately eight hours and then poured into forty milliliters of ice-water whereupon a solid precipitates. The thusobtained mixture is stirred for two hours. The solid product is recovered ,byfiltration, washed with water, dried and recrystallized from ether-hexane to give crystals of6'u fluoro -'115,175 'dihydroxy 4 androsten-3-one l7-acetate, Compound Iaf (ester 1 Similarly, by reacting Compound Iaf with the appropriate hydrocarbon carboxylic acids, or the acid anhy drides and acid halides thereof, there are produced other 17 L acylates of 6a fluoro 115,175 dihydroxy 4- androsten 3 one such as 60: -fluoro 115,175-dihydroxy- 4 androsten 3 one 17 formate, 6oz fluoro- 115,175 dihydroxy 4 androsten-3-one 17-propionate, 6a, fluoro 115,175 dihydroxy 4 androsten 3 -one 17 butyrate, 6a fluoro 115,175 dihydroxy 4 androsten 3 one 17 valerate, 6oz fluoro 115,175-diliydroxy 4 androsten 3 one 17 hexanoate, 6afluoro 115,175 dihydroxy 4 androsten 3 one 17- laurate, 6m fluoro 115,175 dihydroxy 4 androsten- 3 one 17 trimethylacetate, 6a fluoro 115,175-dihydroxy 4 androsten 3 one 17 isobutyrate, 6ozfluoro 1 115,175 dihydroxy 4 androsten 3 one 17- isovalerate, 6oz fluoro 115, 175 dihydroxy 4 androsten 3 one 17 tertiary butylacetate, 6a-fluoro- 115,l75 dihydroxy 4 androsten 3 one 17-(5- cyclopentylpropionate), 6a fluoro 115,175 dihydroxy 4- androsten 3 one 17 cyclohexane-carboxylate, 60t-flll01'0- 115,175 dihydroxy 4 androsten 3 one 17 cyclohexylacetate,'6u fluoro 115,175 dihydroxy 4 androsten 3 one 17 benzoate, 6oz fluoro 115,175- dihydroxy -4 androsten 3 one 17 phenyl-acetate, 6oz fluoro 115,175 dihydroxy 4 androsten 3 one 17 (5 phenylpropionate), 6a fluoro 115,175-dihydroxy 4 androsten 3 one 17-(o-, .m-, p-toluate), 6afliioro 115,175 dihydroxy 4 androsten 3 one 17- hemisuccinate, 6a fluoro 115,175 dihydroxy 4 androsten- 3 one 17 hemiadipate,'6a fluoro 115,175- dihydroxy 4 androsten 3 one 17-acrylate, 6oi-fluoro- 115 ,175 dihydroxy 4 androsten 3 one l7-crotonate,

Chou fluoro 30 fluoro 115,175 dihydroxy- 4 androsten 3 one 17 i cinnamate, 6a fluoro 115,175- dihydroxy 4- androsten 3 one 17-maleate, and 6u-fluoro-115',175- dihydroxy-4-androsten-3-one 17-citraconate. I If the corresponding acylating agent is solid an inert solvent such as toluene, xylene, or dioxane can be added to effect solution and to provide a liquid esterification medium. I

If the esterifying agent is the free acid, the reaction is carried out in the presence of an esterification catalyst.

E. 611 fluoro 175 hydroxy 4 androstene-3,11-dione 17-acetate [Compound 1ab (ester A solution of 148 milligrams of Compound Iaf (ester in eight milliliters of glacial acetic acid is treated with a solution of 74 milligrams of chromic anhydride in 0.4 milliliter of water and eight milliliters of acetic acid for five hours at room temperature. There is then added two milliliters of methyl alcohol, the mixture is concentrated in vacuo and the residue obtained is diluted with water followed by extraction with ether. The ether solution is washed with successive portions of dilute aqueous sodium carbonate solution, followed by removal of the water and ether to leave a residue. .The residue is recrystallized from ether-Skellysolve B hexanes to give 60:- fiuoro 175 hydroxy 4 androstene 3,11 dione 17- acetate, Compound Iab (ester a crystalline solid.

One gram of Iab (ester dissolved in fifty milliliters of methyl alcohol is treated with 8.25 milliliters of 0.5 N

' sodium hydroxide solution (aqueous) and the mixture is 6b: fluoro 115,175 1 dihydroxy 4- androsten 3 one allowed to standat' room temperature for approximately 48 hours. One drop of acetic acid is added and the mix ture is concentrated to dryness under reduced pressure. The residue is recrystallized from aqueous acetone to give crystals of 6a fluoro hydroxy-4-androstene- 3,11-dione, Compound Iotb PREPARATION A 1. The 3-ethylene ketal of methyl 3,11-diketo-5u',6aepoxy-1 7 (20) [cis] -pregnen-21 -oate To a solution of 5.0 grams of the 3-ethylene glycol ketal of methyl 3,11-diketo-4,l7(20)-[cisl-pregnadien- 21-oate, prepared in the manner described in U. S. Patent 2,707,184, in 100 milliliters of chloroform was added a chilled solution of 1.9 grams of perbenzoic acid dissolved in 31.5 milliliters of chloroform. The solution was maintained at about four degrees centigrade for 24 hours, and then at room temperature for 72 hours. The solution was then washed with a five percent aqueous solution of sodium bicarbonate and then with water. The chloroform layer was separated, dried, and the solvent distilled to give a residue of 5.3 grams of solid. Crystallization of this solid from methanol gave 2.24 grams of product melting at to degrees centigrade and after two crystallizations from methanol, there was obtained pure 3-ethylene ketal of methyl 3,11-diketo-5a,6a-epoxy- 17 (20)-[cisl-pregnen-21-oate melting at 206 to 209 degrees centigrade having an [@1 of plus 37 degrees (CHCl and having the analysis given below:

Analysis.Calcd. for C I-1 0 C, 69.20; H, 7.75. Found: C, 69.59; H, 7.81.

2. Methyl 3,1 I -diket0-5 (1,6 5-dihydroxy-1 7 (20) -allopregnen-21-oate and methyl 3,11 -diketo-5a-hydr0xy-65- fluoro-1 7(20 -all0pregnen-21 -0ate To a solution of 1.73 grams of 3-ethylene ketal of methyl 3,11-diketo-5a,6a-epoxy-17(20)-[cisl-pregnen-21- oate in sixteen milliliters of methylene chloride was added six milliliters of 48 percent hydrofluoric acid. The hetero geneous mixture was stirred for two hours, made slightly basic with 300 milliliters of five percent sodium bicar: bonate solution, and extracted with methylene chloride.

The extract was washed, dried, and evaporated to dryness to give 1.62 grams of crude solid. Chromatography gave two fractions: A, .481 milligrams eluted 'with mjethylene chloride plus five percent acetone and B, 921 milligrams eluted with methylene chloride plus ten and twenty percent acetone. Crystallization of Fraction A from acetone-Skellysolve B hexanes gave 390 milligrams of methyl 3, l l-diketo-5a-hydroxy-6p-fluoro-17 (20) -allopregnen- 2'l-oate, melting point 254 to 260 degrees Centigrade. An analytical sample melted at 260 to 263 degrees centigrade.

Analysis.-Calcd. for C H O F: F, 4.84. F, 4.47.

Fraction B, on crystallization from acetone-Skellysolve B hexanes, gave 470 milligrams of methyl 3,1l-diket- 50:,6/3-CllhYdI0XY 17(20) allopregnen-Zl-oate, melting point 235 to 245 degrees centigrade. An analytical sample melted at 245 to 2.48 degrees centigrade.

Analysis.--Calcd. for C H O C, 67.67; H, 7.74. Found: C, 67.91; H, 7.62.

3. Methyl 3,1]-diketo-m-hydr0xy-6flrflu0ro-1 7(20) -allopregnen-ZI -0'ate 3-ethylene ketal Found:

A mixture of 1.9 grams of methyl 3,11-diketo-5ahydroxy-6 8-fiuoro- 17 (20) -allopregnen-2 l-oate, 59 milligrams of p-toluenesulfonic acid monohydrate and 31 milliliters of distilled ethylene glycol was added to 800 milliliters of benzene. The mixture was stirred and refluxed for two hours, with the condensate passing through a water trap to remove the water. After reflux the mixture was cooled, washed with water, and evaporated to dryness to give a crude solid which on recrystallization from acetone-Skellysolve B hexanes gave 1.96 grams of methyl 3 1 l-diketo-S a-hydroxy-6fi fiuoro-17 (20) -allopre gnen-2l-oate 3-ethylene ketal, melting point 170 to 173 degrees centigrade.

Following the above procedure, substituting other dihydric alcohols for ethylene glycol, ,for example, 1,2- propylene glycol, 2,3-butanediol, 1,3-butanediol and 2,3- pentanediol is productive of the respective 3-alkylene ketals of methyl 3,11-diketo-5a-hydroxy-6t3-fluoro- 17(20)-allopregnen-2l-oate.

4. 5 01,1 1 8,21 -trihyclr0xy-6 ti-fluoro-J 7(20)-allopregnen-3- one 3-ethylene ketal To a solution of 1.96 grams of methyl 3,1l-diketo-5ahydroxy-6B-fluoro- 17 (20) -allopregnen-21-oate 3-ethylene ketal in 850 milliliters of anhydrous ether was added 3.7 grams of lithium aluminum hydride and the mixture was stirred for a period of one hour. 200 milliliters of water was added slowly and the ether phase separated. The aqueous phase was extracted with ethyl acetate and the extracts added to the ether phase. The combined ether-ethyl acetate solution was washed with water, dried and evaporated to dryness under reduced pressure. The crude solid residue was crystallized from acetone-Skellysolve B hexanes to give 1.30 grams of 5a,1lfi,21-tllhydroXy-6,8-i'luoro-l7 (20) -allopregnen-3-one I i-ethylene ketal, melting point 197 to 205 degrees centigrade. An additional 226 milligrams was obtained from the mother liquor, melting point 175 to 185 degrees centigrade.

The acetate was prepared by allowing 0.87 gram of 5 (1,1 1,6,2l-trihydroxy-6/3-fiuoro-17(20)-allopregnen-3- one 3-ethylene ketal to stand overnightin ten milliliters of acetic anhydride and ten milliliters of pyridine. The solution was then poured into ice water to give 0.92 gram of 50.,1lfi-dihydroxy-6B-fiuoro 21 acetoXy-17(20)-allopregnen-B-one I l-ethylene ketal, melting point 140 to 150 degrees centigrade, which on recrystallization from acetoneSkellysolve B hexanes gave 0.77 gram, melting point 149 to 153 degrees centigrade.

Similarly, other 21-organic carboxylic .esters of 5a,l1;8,21-trihydroxy 613 fluoro-17(20)-allopregnen-3- one S-ethylene ketals are prepared wherein the 21-acyloxy group is formyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoy loxy, phenylacetoxy, or the like, by contacting 51 ,115,21- trihydroxy-6fl-fluoro- 17 20 -allopregnen-3-one 3- ethylene ketal with an appropriate acylating agent, e. g., the anhydride or acid halide of the selected acid in a solvent such as, for example, benzene, toluene, pyridine, or the like.

6. 5 0:,1 113,17a-trihydr0xy-6fZ-fluoro-21-zzcet0xyallopregnane-3,20-dione 3-ethylene ketal To a solution of 0.77 gram of SaJlfl-dihydroxy-dflfiuoro 21 acetoxy-17(20)-allopregne n-3-0ne 3-ethylene ketal in 35 milliliters of tertiary butyl alcohol was added one milliliter of pyridine, 1.9 milliliters of N-methylmorpholine oxide peroxide solution, and 13.1 milligrams of osmium tetroxide (9.- milliliters of tertiary butyl alcohol solution containing 1.44 milligrams OsO per milliliter). The solution was stirredfor a period of 2.5 hours, fifteen milliliters of five percent sodium hydrosulfite added, stirred for an additional ten minutes, 0.7 gram of finely ground synthetic magnesium silicate added, stirred for a period of twenty minutes more and filtered. The filtrate was taken to dryness under reduced pressure (below fifty degrees centigrade) and the residue dissolved in methylene chloride, washed with water, dried and evaporated to dryness. This residue was crystallized from acetone-Skellysolve B hexanes to give 0.47 gram of 5a,11/3,17a-trihycl roxy 65 fiuoro 21-acetoxyallopregnane-3,20rdione 3- ethylene ketal, metling point 220 to 228 degrees centigrade.

A solution of 0.47 gram of 5a,11;6,17pe-trihydroxy-6B- fiuoro-Zl-acetoxyallopregnane-3,20-dione 3-ethylene ketal in 35 milliliters of acetone and four milliliters of 1N sulfuric acidsolution was gently boiled on the steam bath for ten minutes, cooled and neutralized with dilute sodium bicarbonate solution. Addition of water and cooling gave 0.33 gram of 5a,].1B,l7oz-t1ihYdIOXY-6B-fill0lO-2lacetoxyallopregnane-3,20-dione, melting-point 230 to 240 degrees centigrade.

A solution of milligrams of 5oz,1 1fi,17oc-tl'ihyd1'OXy- 6fi-fluoro-2l-acetoxyallopregnane-3,20-dione in 4.9 milliliters of acetic acid and 0.1 milliliter of water wasrefluxed for a period of one hour, cooled, diluted with fifty milliliters of water and evaporated to dryness under reduced pressure. The residue was .chromatographed over Florisil (synthetic magnesium silicate) to give one fraction (77 milligrams) eluted with methylene chloride plus .ten percent acetone. Crystallization from acetone-Skellysolve B hexanes gave 38 milligrams of 6B-fluoio-ll;8, l7qzdihydroxy-Z1-acetoxy-4-pregnene-3,20-dione (6/3 fluorohydrocortisone acetate), meltingpoint 210to 218 degrees centigrade. Infrared data and ultraviolet data were found to be in agreement with the structure.

9. Isomerization of 6,3- to 6a-fluorohydroco rtisone acetate A solution of 0.132 gram of .6fl-fluorohydrocortisone acetate in twelve milliliters of chloroform and 0.1 milliliter-of absolute alcohol was cooledto minus ten degrees centigrade in an ice-salt bath and a stream of anhydrous hydrochloric acid was gently bubbled through the solution for 2.5 hours while the temperature was maintained between minus five and minus fifteen degrees centigrade. The solution was then diluted with 25 milliliters of chloroform, washed with dilute sodium bicarbonate and water, dried over anhydrous sodium sulfate,,and evaporatedto dryness under reduced pressure .atsixty degrees .centi- 33 grade or less. Crystallization of the residue from acetone- Skellysolve B gave 42 milligrams of product, 6ot-flL1OIO- hydrocortisone acetate, melting point 203 to 210 degrees centigrade.

10. 60c fluoro 115,17a,21-trihydroxy-4-pregnene-3,20- dione (ou-fluorohydrocortisone) (Compound XX) A solution of 1.1 grams of 6ot-fluorohydrocortisone acetate, 1.0 grams of potassium bicarbonate, 100 milliliters of methanol, and fifteen milliliters of Water was purged with nitrogen and stirred at approximately 25 de grees centigrade for several hours. The solution was then neutralized by addition of acetic acid and the methanol was removed by distillation under reduced pressure. The residue was extracted with 100 milliliters of methylene dichloride and the extract, after drying over sodium sulfate, was chromatographed over a column of eighty grams of synthetic magnesium silicate. The product fraction was eluted with Skellysolve B hexanes plus twenty and thirty percent acetone and gave 770 milligrams of 'ea-fiuorohydrocortisone, Compound XX, which melted at 192 to 195 degrees centigrade after crystallization from ethyl acetate-Skellysolve B hexanes. An analytical sample melted at 192 to 201 degrees centigrade and had a rotation of [:1 plus 127 degrees (chloroform).

AnaIysis.Calcd. for C H O F: C, 66.29; H, 7.68; F, 4.99. Found: C, 66.28; H, 7.65; F, 4.43.

EXAMPLE 22 60c fluoro 11B 11ydroxy-4-androstene-3,17-rlione (Compound 11x8 A mixture of seven grams of Compound XX (obtained according to the procedure disclosed in Preparation A, above), 125 milliliters of glacial acetic acid and fifty milliliters of water is treated with thirty grams of analytical reagent sodium bismuthate and shaken vigorously at room temperature for approximately 45 minutes. While cooling the thus-obtained reaction mixture in an ice-bath, a solution of 120 grams of potassium hydroxide in 600 milliliters of water and 150 milliliters of methylene chloride is added thereto. After stirring for approximately thirty minutes 100 grams of diatornaceous earth filter aid is added, the mixture is filtered, and the cake washed well with methylene chloride. The filtrate and wash are combined and upon standing layer separation occurs. The organic layer is separated, washed with potassium hydroxide solution and water, and dried over sodium sulfate. Evaporation of the solvent gives a solid residue which is then recrystallized from methylene chloride-hexone to give 6a-fluoro-1lfl-hydroxy-4-androstene-3,17-dione, Compound Inte a crystalline solid product.

Compound Inte is then treated according to the procedure disclosed in Example 21, Parts C through F, to obtain in succession Compounds th, Iaf (ester Iab (ester and 10519;.

EXAMPLE 23 6u-flu0ro-4-androstene-3,11,17-trione (Compound Iocd EXAMPLE 24 6a-fluoro-4-androstene-3,11,17-trione (Compound lad from 6a-flu0ro-1 1,8,1 70,21-trihydroxy-4-pregnene-3,20- dione (Compound XX) Compound XX is treated according to the procedure disclosed in Example 22 (first paragraph) to obtain Compound Inte Compound Iae is then treated according to the procedure disclosed izt Example 23 to obtain 60:- fiuoro-4-androstene-3,11,17-trione, Compound Iocd PREPAR ATION B l. 19-nor-5-androstene-3J1 ,1 7 -trione 3-1 7-bis-(ethylene ketal) A mixture of five grams of l9-nor-4-androstene-3,l 1,17 trione (U. S. Patent 2,757,186), 250 milliliters of benzene, twenty milliliters of ethylene glycol and 150 milligrams of p-toluenesulfonic acid is vigorously stirred and heated at reflux under a water trap until the reaction is complete. The reaction mixture is cooled, washed with five percent aqueous sodium carbonate solution and water and dried over sodium sulfate. Evaporation of the solvent gives a crude residue of 19-nor-5-androstene-3,- 11,17-trione 3,17-bis-(etl1ylene ketal).

2. 1 1 fl-hydroxy-l 9-nor-5-andr0stene-3,1 7-dione 3,1 7-bis- (ethylene ketal) The total crude residue obtained in Preparation B, Part 1, above, is dissolved in fifty milliliters of tetrahydrofuran and added with stirring over approximately a five minute period, under nitrogen, to a mixture of two grams of lithium aluminum hydride and milliliters of anhydrous ether. The mixture is stirred whilst ice cooling, followed by careful treatment of the mixture with twenty milliliters of water. The mixture is then diluted with 200 milliliters of ether, stirred and filtered to remove inorganic solids. The filtrate is washed with three fiftyrnilliliters portions of water, dried over sodium sulfate, and the mixture taken to dryness. The residue is recrystallized from other to give 1lB-hydroxy-19-nor-5-androstene-3,l7-dione 3,17-bis-(ethylene ketal), a crystalline solid.

3. 5 0t,6tX-6I)0xy-1 IB-hydroxy-l9-norandr0stane-3,17-di0ne 3,17-bis-(ethylene ketal) A mixture of two grams of llB-hydroxy-l9-nor-5-androstene-3,l7-dione 3,l7-bis-(ethylene ketal), forty milliliters of chloroform and 0.4 gram of sodium acetate is cooled in an ice-water bath and treated with four milliliters of forty percent peracetic acid. The cooled mixture is stirred vigorously for several hours. The cold bath is then removed and the mixture is stirred with forty milliliters of saturated aqueous sodium bicarbonate solution for one hour and upon being allowed to stand layer separation occurs. The chloroform layer is sepa rated, washed twice with water, dried over sodium sulfate and the solvent removed by distillation. The residue is recrystallized from ether to give 511, 6a-expoxy- 1 LB-hydroxy-l9-norandrostane-3, l7-dione 3, l7-bisethylene ketal), Compound XVIII a crystalline solid.

EXAMPLE 25 A. 6,8-fluoro-5 00,1 1 ,B-dihydroxy-I 9-norandrostane-3 ,1 7-dione (Compound XIX A stoichiometric equivalent amount of Compound XVIII obtained according to the procedure of Preparation B, Parts 1 through 3, above, is substituted for Compound XVIII in the procedure of Example 21, Part A, to obtain a crude residue of B-fl1l()1O-5oc,l1,8-Cllhydr0Xyl9-norandrostane-3,l7-dione, Compound XIX B. 6a-fluoro-11B-hydroxy-19-nor-4-androstene-3J 7 -dione (Compound Iote The crude residue of Compound XIX is substituted for the crude residue of Compound XIX in the procedure of Example 21, Part B, to obtain crystals of 6u-fiuoro-.

1 1fl-hydroxy-l9-nor-4-androstene 3 ,17-dione, Compound 10622. 7

C. 6ot-fluoro-11p,I7p-dihydroxy-19-nor-4-androsten-3-bne (Compound I of A stoichiometric equivalent amount of Compound Iae 35 is substituted for Compound Iae in the procedure of Example 21, Part C, to obtain crystals of 6m-fluoro-11B,17fidihydroxy-l9-nor4 androsten-3-one, Compound locf A stoichiometric equivalent amount of Compound Iaf is substituted for Compound Iocf in the procedure of Example 21, Part D, to obtain 6a-fluoro-11;8,17fl-dihydroxy- 19-nor-4-androsten 3 one 17-acetate, Compound leafy (ester Similarly by reacting Compound Ictf with the appropriate hydrocarbon carboxylic acids (in the presence of an esterification catalyst), or the acid anhydrides and acid halides thereof, such as those named above, there are produced other 17-acylates of 6a-fluoro-1lfi,17,B-dihydroxy-l9-nor-4-androsten-3-one such as, for example, the 17-propionate, the 17-hemisuccinate, and the 17-benzoate.

E. 6 a-fluoro-I 7/3-hydr0xy-1 9-nor-4-androstene-3 ,1 1 -dine 17-acetate [Compound locb (ester A stoichiometric equivalent amount of Compound Iccf (ester is substituted for Compound Iaf (ester in the procedure of Example 2], Part E, to obtain crystals of 6a-fluoro-17fi-hydroxy-19-nor-4-androstene-3,l l-dione l7- acetate, Compound Iocb (6Ste1' pounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim: 1. A 6-fiuoro compound of the androstane series having the formula:

F wherein R is selected from the group consisting of methyl and hydrogen, R is selected from the group consisting of hydroxyl, OAcyl, and keto, the term Acyl representing the acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, and Z is selected from the group consisting of hydrogen, hydroxyl, and keto.

. 6-fluoro-17/3-hydroxy-4-androsten-3-one. Got-fluoro-17,6-hydroxy-4-androsten-3-one. 6,3-fluoro-17fl-hydroxy-4-androsten-3-one. 6-fluoro-4-androstene-3,17-dione. 6a-fluoro-4-androstene-3,17-dione. 6/8-fiuoro-4-androstene-3,17-dione.

8. 6-fiuoro-l7/i-hydroxy-4-androstene-3,1 l-dione. 9. 6u-fluoro-17fl-hydroxy-4-androstene-3,1l-dione.

. 6fl-fiuoro-17,3-hydroxy-4-androstene-3, 1 l-dione. 6-fluoro-4-androstene-3,l1,17-trione. 6a-fluoro-4-androstene-3 ,1 1,17-trione. 6fi-fiuoro-4-androstene-3 ,1 1,17-trione. 6a-fluoro-l 1fl-hydroxy-4-androstene-3 l 7-dione. 6ez-fil101'O-1 1 3,17fl-dihydroxy-4-androsten-3-one.

16. 6-fiuoro-17fi-hydroxy-4-androsten-3-one l7-acylatc in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve'carbon atoms, inclusive.

l7. 6a-fiuoro-17fi-hydroxy-4-androsten-3-one pionate.

l8. 6,6-fluoro-17fl-hydroxy-4-androsten-3-one 17 propionate.

19. 6oa-fluoro-1 1 fl,l7/3-dihydroxy-4-androsten-3-one l7- acylate in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

2(). 6a-fluoro-1lfi,17/3-dihydroxy-4-androsten-3-one 17- propionate.

21. 6-fluoro-17B-hydroxy-4-androstene-3,ll-dione l7- acylate in which the acyl radical is that of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive.

22. 6a-lluoro-17;9-hydroxy-4-androstene-B,ll-dione l7- propionate.

23. 6fl-fluoro-l7fl-hydroxy-4-androstene-3,1l-dione 17- propionate.

24. A 6-fluoro-5-hydroxy compound of the androstane series having the formula:

17 prowherein R is selected from the group consisting of methyl and hydrogen, R is selected from the group consisting of hydroxyl, OAcyl and keto, the term Acyl representing an acyl radical of a hydrocarbon carboxylic acid containing from one to twelve carbon atoms, inclusive, W is selected from the group consisting of hydroxyl and keto, and Z is selected from the group consisting of hydrogen, hydroxyl and keto.

26. 6fl-fluoro-5a,175-dihydroxyandrostan-3-one 17-propionate.

27. 6 3-fluoro-5a,17,8-dihydroxyandrostane-3,l l-dione.

28. 6 8 fluoro-5u,17fi-dihydroxyandrostane-3,1l-dione 17-propionate.

29. 613-fluoro-5a-hydroxyandrostane-3, 1 7-dione.

30. 6B-fluoro-5a-hydroXyandrOstane-S,1 1,17-trione.

31. 618-fluoro-3 3,5 or, 17 B-trihydroxyandrostane.

33. A 6-fluoro-11-oxygenated compound of the andro' stane series having the formula:

wherein R is selected from the group consisting of hydrogen and methyl, R is an alkylene radical containing not more than eight carbon atoms, inclusive, and the attaching oxygen to carbon bonds are separated by a chain of at least two and not more than three carbon atoms and W is selected from the group consisting of hydroxyl and keto.

34. 6-fiuoro-5-androstene-3,11,17-trione 3,17-bis-(ethylene ketal).

35. 6-fluoro-11fi-hydroxy-5-androstene-3,17-dione 3,17- bis-(ethylene ketal).

36. A 6-fluoro-11-oxygenated compound of the androstane series having the formula:

wherein R is selected from the group consisting of methyl and hydrogen, and where W is the same member selected from the group consisting of hydroxyl and keto and n and n are whole numbers from one to two, inclusive.

37. 3-(N-pyrro1idinyl)-6-fluoro-3,5-androstadiene 11, l7-dione.

38. 3-(N-pyrro1idinyl)-6-fluoro-l113,17fl-dihydroxy 3, S-androstadiene.

No references cited.

Disclaimer 2,838,492.Raymond L. Pederson and Milton E. H 67'7', Kalamazoo, John 0. Babcock, Portage Township, Kalamazoo County, and J Allan 0am??- bell and John A. H ogg, Kalamazoo, Mich. G-FLUORO STEROIDS. Patent dated June 10, 1958. Disclaimer filed May 20, 1965, by the inventors; the assignee, The Upjohn Company, assenting.

Hereby enter this disclaimer to claims 2, 3, l, 5, 6 and 7 of said. patent.

[Ojficial Gazette August 24, 1.965.] 

1. A 6-FLUORO COMPOUND OF THE ANDROSTANE SERIES HAVING THE FORMULA:
 36. A 6-FLUORO-11-OXYGENATED COMPOUND OF THE ANDROSTANE SERIES HAVING THE FORMULA: 